Whole genome sequencing identifies SCN2A mutation in monozygotic twins with Ohtahara syndrome and unique neuropathologic findings

Abstract

Mutations in SCN2A gene cause a variety of epilepsy syndromes. We report a novel SCN2A-associated epilepsy phenotype in monozygotic twins with tonic seizures soon after birth and a suppression-burst EEG pattern. We reviewed the medical records, EEG tracings, MRI, neuropathological findings, and performed whole genome sequencing (WGS) on Twin B’s DNA and Sanger sequencing (SS) on candidate gene mutations. Extensive neurometabolic evaluation and early neuroimaging studies were normal. Twin A died of an iatrogenic cause at 2 weeks of life. His neuropathologic examination was remarkable for dentato-olivary dysplasia and granule cell dispersion of the dentate gyrus. Twin B became seizure-free at 8 months and was off anti-epileptic drugs by 2 years. His brain MRI, normal at 2 months, revealed evolving brainstem and basal ganglia abnormalities at 8 and 15 months that resolved by 20 months. At 2.5 years, Twin B demonstrated significant developmental delay. Twin B’s WGS revealed a heterozygous variant c.788C>T predicted to cause p.Ala263Val change in SCN2A and confirmed to be de novo in both twins by SS. In conclusion, we have identified a de novo SCN2A mutation as the etiology for Ohtahara syndrome in monozygotic twins associated with a unique dentate-olivary dysplasia in the deceased twin.

SCN2A encephalopathy

“…6,8,[10][11][12][13]15 Despite variability in age at onset and severity of outcome, there are common features in SCN2A encephalopathy. Our patients presented at a median of 2 days with multiple types of brief focal seizures that cluster, reaching maximal frequency of multiple hourly seizures within 3 months of onset.…”

“…[4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] Our analysis suggests that patients fall into 3 phenotypic groups: a severe neonatalinfantile phenotype, an intermediate neonatal-infantile phenotype, and a childhood phenotype (figure 4). The numbers in the latter groups are small; further cases are required to confirm distinct subgroups or, alternatively, a spectrum of severity.…”

“…26,36,38 SCN8A encephalopathy can present with early-onset EE and responds to sodium channel blockers 27,30,39 in contradistinction to SCN1A diseases. 38,40 However, the median age at onset of 5 months for SCN8A is later, [4][5][6][7][8][9][10][11][12][13][14][15][16][17]19,27 which may reflect the respective patterns of expression of the subunits. SCN8A gradually replaces SCN2A as the major subunit in excitatory neurons during maturation.…”

Two Distinct De novo Pathogenic Sequence Variants in the SCN2A Gene in Children with Early Infantile Epileptic Encephalopathy/Ohtahara Syndrome

“…As a result of multi-step analytical process we identified a heterozygous NC_000002.11:g.166166923C>T transition affecting the SCN2A gene resulting in a p.Ala263Val substitution (Figure 1). This variant has been previously detected in patients with neonatal seizures and EIEE/OS [30,31]. To support our assumption of its pathogenicity we performed confirmative analysis by targeted Sanger sequencing in patient 1 and his parents.…”

Genetic Epilepsy Syndromes Without Structural Brain Abnormalities: Clinical Features and Experimental Models

“…Similarly, de novo SCN2A truncating and missense mutations have been identified in early-onset intractable childhood epilepsies, with features ranging from Ohtahara syndrome to Dravet syndrome [80][81][82]. Contrary to BNFIS mutants, functional analysis of some of these mutants using in vitro expression systems has shown loss of function [82], although it is not yet clear how loss of function in a sodium channel predominantly expressed in excitatory neurons can lead to network hyperexcitability.…”